EX 527 (SEN0014196)
(Synonyms: EX-527,SIRT1 Inhibitor III,SEN0014196,EX527, Selisistat) 目录号 : GC10635
EX 527 (SEN0014196) 作为 SIRT1 选择性抑制剂，抑制 Sirt1 的效力比 Sirt2 和 Sirt3 高 100 倍，并且对 Sirt5 的去乙酰化活性没有影响。
Cas No.:49843-98-3
Sample solution is provided at 25 µL, 10mM.
EX 527 (SEN0014196), as a SIRT1-selective inhibitor, inhibits Sirt1 ～100-fold more potently than Sirt2 and Sirt3 and has no effect on Sirt5′s deacetylation activit.The IC50 values for Sirt1 and Sirt3 are 0.09 ± 0.03 μM and 22.4 ± 2.7 μM, respectively. Sir2Tm was also efficiently inhibited by Ex-527 with IC50 of 0.9 ± 0.3 μM.[1]
In vitro experiment it shown that cell viability significantly increased and cell death decreased in cancer cells with SIRT1 silencing or EX 527 (10 μM) treatment compared with the control after exposure to RSL3 or sulfasalazine.[2] In vitro, treatment with 1 μM EX-527 decreased colony formation of ovarian carcinoma cells, with or without overexpression of SIRT172. However, at 600 nM, EX-527 suppressed cell migration and inhibited the occurrence of epithelial–mesenchymal transition (EMT) in chemotherapy resistant oesophageal cancer cells.[4] In vitro experiment it indicated that SIRT 1 inhibition by EX 527 (10 μM) elevated ROS production. SIRT1 and PGC-1α levels were dramatically decreased.[6]
In vivo efficacy test indicated that pharmacological blockade of Sirt-1 with 2 mg/kg EX 527/mouse/day daily for 3 weeks alleviated GVHD without impairing T-cell-mediated GVL activity.[3] In vivo efficacy study demonstrated that treatment with 5 mg/kg EX 527 intraperitoneally in C57BL/6J mice abolished the protective effects of melatonin.[4] In vivo, the data indicated that LPS-induced intrapulmonary inflammation and LPS-induced elevation of 4E-BP1 phosphorylation were attenuated by EX 527 (10 mg/kg, i.p.).[5]
References:
[1]. Gertz M, et al. Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism. Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):E2772-81.
[2]. Lee J, et al. Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer. Redox Biol. 2020 Oct;37:101697.
[3]. Daenthanasanmak A, et al. Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice. Blood. 2019 Jan 17;133(3):266-279.
[4]. Broussy S, et al. Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat). J Enzyme Inhib Med Chem. 2020 Dec;35(1):1124-1136.
[5]. Huang J, et al. The SIRT1 inhibitor EX-527 suppresses mTOR activation and alleviates acute lung injury in mice with endotoxiemia. Innate Immun. 2017 Nov;23(8):678-686.
[6]. Waldman M, et al. Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving 'SIRT1 and PGC-1α'. Cardiovasc Diabetol. 2018 Aug 2;17(1):111.
EX 527 (SEN0014196) 作为 SIRT1 选择性抑制剂，抑制 Sirt1 的效力比 Sirt2 和 Sirt3 高 100 倍，并且对 Sirt5 的去乙酰化活性没有影响。Sirt1 和 Sirt3 的 IC50 值为 0.09 ± 0.03 μM 和 22.4分别为± 2.7 μM。 Sir2Tm 也被 Ex-527 有效抑制，IC50 为 0.9 ± 0.3 μM。[1]
体外实验表明，与暴露于 RSL3 或柳氮磺胺吡啶后的对照相比，SIRT1 沉默或 EX 527 (10 μM) 处理的癌细胞的细胞活力显着增加，细胞死亡减少。[2] 在体外，用 1μM EX-527 处理可减少卵巢癌细胞的集落形成，有或没有 SIRT172 过表达。然而，在 600nM 时，EX-527 抑制细胞迁移，抑制化疗耐药食管癌细胞上皮-间质转化 (EMT) 的发生。[4] 体外实验表明 SIRT 1 抑制EX 527 (10 μM) 提高了 ROS 的产量。 SIRT1 和 PGC-1α 水平显着降低。[6]
体内药效试验表明，每天 2 mg/kg EX 527/小鼠/天对 Sirt-1 进行药理学阻断，持续 3 周可减轻 GVHD，而不会损害 T 细胞介导的 GVL 活性。[3] 体内功效研究表明，在 C57BL/6J 小鼠中腹膜内注射 5 mg/kg EX 527 可消除褪黑激素的保护作用。[4] 在体内，数据表明 LPS 诱导的肺内EX 527（10mg/kg，i.p.）减弱了炎症和 LPS 诱导的 4E-BP1 磷酸化升高。[5]
| Cell experiment [1]: | |
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Cell lines |
T cells |
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Preparation Method |
Purified WT or Sirt-1−/− T cells were labeled with CFSE and cocultured with T-cell-depleted splenocytes as APCs from BALB/c mice for 5 days in the presence of either dimethyl sulfoxide or EX 527 (10 µg/mL). Cells were restimulated with phorbol 12-myristate 13-acetate and ionomycin for cytokine measurement. |
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Reaction Conditions |
10 µg/mL, 5 days |
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Applications |
T cells with allogeneic antigen-presenting cells (APCs) in vitro, and found that EX 527 significantly reduced CD4 T-cell proliferation and IFN-γ production to a comparable level of Sirt-1−/− T cells. |
| Animal experiment [2]: | |
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Animal models |
Male ZDF rats (body weight 300 ± 25 g) |
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Preparation Method |
EX-527 (5 μg/kg, twice weekly) was administered intraperitoneally (i.p.) to HFD-fed rats for ten weeks. The normal diet-fed rats received diets which were devoid of fats. Glucose levels were determined by using a glucometer. |
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Dosage form |
5 μg/kg, i.p. |
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Applications |
Two weeks after HFD-feeding, blood glucose concentration was increased significantly in HFD fed rats than that of normal diet-fed rats. However, fasting blood glucose level was dramatically decreased in the HFD-fed rats following EX 527 treatment. |
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References: [1]. Daenthanasanmak A, et al. Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice. Blood. 2019 Jan 17;133(3):266-279. [2]. Kundu A, et al. EX-527 Prevents the Progression of High-Fat Diet-Induced Hepatic Steatosis and Fibrosis by Upregulating SIRT4 in Zucker Rats. Cells. 2020 Apr 29;9(5):1101. |
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| Cas No. | 49843-98-3 | SDF | |
| 别名 | EX-527,SIRT1 Inhibitor III,SEN0014196,EX527, Selisistat | ||
| 化学名 | 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide | ||
| Canonical SMILES | C1CC(C2=C(C1)C3=C(N2)C=CC(=C3)Cl)C(=O)N | ||
| 分子式 | C13H13ClN2O | 分子量 | 248.71 |
| 溶解度 | ≥ 12.4 mg/mL in DMSO, ≥ 25.45 mg/mL in EtOH with ultrasonic | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.0207 mL | 20.1037 mL | 40.2075 mL |
| 5 mM | 0.8041 mL | 4.0207 mL | 8.0415 mL |
| 10 mM | 0.4021 mL | 2.0104 mL | 4.0207 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
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- Purity: >98.00%
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Related Biological Data
EX527 abrogated the inhibitory effect of DAPA on Ang II-induced ER stress in cardiomyocytes. a, b The protein levels of Bcl-2, Bax, and cleaved caspase 3 in each group were detected.
Thapsigargin (TG), EX527, and DAPA were purchased from Glpbio (Montclair, CA, USA).
Acta Pharmacol Sin (2021): 1-12. PMID: 34853445 IF: 6.152 -
Related Biological Data
Upregulation of SIRT1 ameliorates TNBS-induced colitis, whereas blockade of SIRT1 aggravates TNBS-induced colitis in mice. Three groups of TNBS-exposed mice were treated with Cay10591 (4.5 mg/kg), EX527 (10 mg/kg), or PBS as controls by oral gavage.Three groups of TNBSexposed mice were also treated with CX4945 or PBS as negative controls.
The SIRT1-specific activator Cay10591 (4.5 mg/kg) and selective inhibitor EX527 (GlpBio) (10 mg/kg) were then administrated by oral gavage individually.
Inflammatory Bowel Diseases (2021). PMID: 34904630 IF: 5.322 -
Related Biological Data
6-Gingerol reduces TGF-β1-induced lung fibroblast proliferation and inflammatory and fibrotic matrix protein deposition by activating SIRT1. (D) The expression levels of TNF-α, IL-1β, and IL-6 in the different groups of cells were determined using RT-qPCR.
Other experimental groups were exposed to 10 ng/mL TGF-β1 and 6-gingerol (10 or 20 μM) or EX-527 (GlpBio) (10 μM).
Allergol Immunopath 50.2 (2022): 104-114. PMID: 35257553 IF: 1.667